Isoquinolinesulfonamide derivatives

ABSTRACT

This invention relates to novel isoquinolinesulfonamide derivatives of Formula (I): ##STR1## wherein A is a C 0-10  alkylene group or a C 0-10  alkylene group having a C 1-10  alkyl group, a phenyl group, a substituted phenyl group or a phenylalkyl group; R 1  and R 2  each is a hydrogen atom; or R 1  and R 2  are linked directly to form an ethylene group unsubstituted or substituted with a C 1-4  alkyl group; 
     R 3  and R 4  each is a hydrogen atom, a C 1-6  alkyl group or linked directly to form a C 2-6  alkylene group; and the pharmaceutically acceptable acid addition salt thereof, and to a process for preparing them. The isoquinoline derivatives possess a relaxatory action for vascular smooth muscle and action for increasing blood flow and are useful as a vasodilator and a hypotensor.

This is a division of application Ser. No. 548,722, filed Nov. 4, 1983now U.S. Pat. No. 4,634,770.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel isoquinolinesulfonamide derivativeswhich possess a relaxatory action for vascular smooth muscle and actionfor increasing blood flow and are useful as a vasodilator and ahypotensor, and a process for the preparation thereof.

SUMMARY OF THE INVENTION

According to the present invention in one embodiment there is providedan isoquinoline derivative of Formula (I): ##STR2## wherein A is a C₀₋₁₀alkylene group or a C₀₋₁₀ alkylene group having a C₁₋₁₀ alkyl group, aphenyl group, a substituted phenyl group or a phenylalkyl group; R₁ andR₂ each is a hydrogen atom; or R₁ and R₂ are linked directly to form anethylene group unsubstituted or substituted with a C₁₋₄ alkyl group;

R₃ and R₄ each is a hydrogen atom, a C₁₋₆ alkyl group or linked directlyto form a C₂₋₆ alkylene group; and the pharmaceutically acceptable acidaddition salt thereof.

The present invention in another embodiment provides a process ofpreparing the above described isoquinolinesulfonyl derivative.

DETAILED DESCRIPTION OF THE INVENTION

Exemplary A groups in Formula (I) include C₀₋₁₀ alkylene groups,preferably C₂₋₆ alkylene groups, such as ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene; and C₁₋₁₀ alkylene groupspreferably C₂₋₆ alkylene groups, substituted by C₁₋₁₀ alkyl group suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,n-pentyl, n-hexyl and n-octyl, a phenyl group, a substituted phenylgroup or a phenylalkyl group such as benzyl and phenylethyl. In thecompound of Formula (I), adjacent nitrogen atoms neighbor to A may belinked directly not through A. Direct linkage between the nitrogen atomsadjacent A in Formula I occurs when A is Co since there are then nocarbon atoms between the nitrogen atoms adjacent A in Formula I. The R₁and R₂ groups in Formula (I) each is a hydrogen atom; or R₁ and R₂ arelinked directly to form an ethylene group. And 5- to 7-memberedheterocyclic rings may be formed through an ethylene group and adjacentnitrogen atoms. Exemplary 5- to 7-membered heterocyclic rings includepiperazine rings and homopiperazine rings. The ethylene groups formed byR₁ and R₂ may be substituted with a C₁₋₄ alkyl group. Exemplarysubstituents include methyl group, ethyl group, n-propyl group,isopropyl n-butyl group, isobutyl group, sec-butyl group. Exemplary R₃and R₄ in Formula (I) include a hydrogen atom, a C₁₋₆ alkyl group, suchas a methyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, isobutyl group, n-hexyl group. The R₃ and R₄ may be linkeddirectly to form a C₂₋₆ alkylene group, preferably ethylene group ortrimethylene group. When R₃ and R₄ are the ethylene group, ##STR3##forms an imidazoline ring. And when they are a trimethylene group, itforms a pyrimidine ring.

Exemplary isoquinolinesulfonamide derivative of the invention include:

(1) N-Guanidino-5-isoquinolinesulfonamide [referred to as "Compound(1)"];

(2) N-(2-Guanidinoethyl)-5-isoquinolinesulfonamide [referred to as"Compound (2)"];

(3) N-(3-Guanidinopropyl)-5-isoquinolinesulfonamide [referred to as"Compound (3)"];

(4) N-(4-Guanidinobutyl)-5-isoquinolinesulfonamide [referred to as"Compound (4)"];

(5) N-(5-Guanidinopentyl)-5-isoquinolinesulfonamide [referred to as"Compound (5)"];

(6) N-(6-Guanidinohexyl)-5-isoquinolinesulfonamide [referred to as"Compound (6)"];

(7) N-(8-Guanidinooctyl)-5-isoquinolinesulfonamide [referred to as"Compound (7)"];

(8) N-(10-Guanidinodecyl)-5-isoquinolinesulfonamide [referred to as"Compound (8)"];

(9) N-[(2-Guanidino-1-methyl)ethyl]-5-isoquinolinesulfonamide [referredto as "Compound (9)"];

(10) N-[(1-Guanidinomethyl)propyl]-5-isoquinolinesulfonamide [referredto as "Compound (10)"];

(11) N-[(1-Guanidinomethyl)butyl]-5-isoquinolinesulfonamide [referred toas "Compound (11)"];

(12) N-[(1-Guanidinomethyl-2-methyl)propyl]-5-isoquinolinesulfonamide[referred to as "Compound (12)"];

(13) N-[(1-Guanidinomethyl)pentyl]-5-isoquinolinesulfonamide [referredto as "Compound (13)"];

(14)N-[(2,2-Dimethyl-1-guanidinomethyl)propyl]-5-isoquinolinesulfonamide[referred to as "Compound (14)"];

(15) N-[(1-Guanidinomethyl-2-methyl)butyl]-5-isoquinolinesulfonamide[referred to as "Compound (15)"];

(16) N-(2-Guanidinopropyl)-5-isoquinolinesulfonamide [referred to as"Compound (16)"];

(17) N-(2-Guanidinobutyl)-5-isoquinolinesulfonamide [referred to as"Compound (17)"];

(18) N-(2-Guanidinopentyl)-5-isoquinolinesulfonamide [referred to as"Compound (18)"];

(19) N-(2-Guanidino-3-methylbutyl)-5-isoquinolinesulfonamide [referredto as "Compound (19)"];

(20) N-(2-Guanidinohexyl)-5-isoquinolinesulfonamide [referred to as"Compound (20)"];

(21) N-(2-Guanidino-3-methylpentyl)-5-isoquinolinesulfonamide [referredto as "Compound (21)"];

(22) N-[(3,3-Dimethyl-2-guanidino)butyl]-5-isoquinolinesulfonamide[referred to as "Compound (22)"];

(23) N-(2-Guanidino-1-phenylethyl)-5-isoquinolinesulfonamide [referredto as "Compound (23)"];

(24) N-(2-Guanidino-1-benzylethyl)-5-isoquinolinesulfonamide [referredto as "Compound (24)"];

(25) N-(2-Guanidino-2-phenylethyl)-5-isoquinolinesulfonamide [referredto as "Compound (25)"];

(26) N-(2-Guanidino-3-phenylpropyl)-5-isoquinolinesulfonamide [referredto as "Compound (26)"];

(27) N-(3-Guanidino-1-methylpropyl)-5-isoquinolinesulfonamide [referredto as "Compound (27)"];

(28) N-(3-Guanidino-2-methylpropyl)-5-isoquinolinesulfonamide [referredto as "Compound (28)"];

(29) N-(3-Guanidinobutyl)-5-isoquinolinesulfonamide [referred to as"Compound (29)"];

(30) N-(3-Guanidino-1-phenylpropyl)-5-isoquinolinesulfonamide [referredto as "Compound (30)"];

(31) N-(3-Guanidino-2-phenylpropyl)-5-isoquinolinesulfonamide [referredto as "Compound (31)"];

(32) N-(3-Guanidino-3-phenylpropyl)5-isoquinolinesulfonamide [referredto as "Compound (32)"];

(33) N-(3-Guanidino-1-benzylpropyl)-5-isoquinolinesulfonamide [referredto as "Compound (33)"];

(34) N-(3-Guanidino-2-benzylpropyl)-5-Isoquinolinesulfonamide [referredto as "Compound (34)"];

(35) N-(3-Guanidino-4-phenylbutyl)-5-isoquinolinesulfonamide [referredto as "Compound (35)"];

(36) N-(4-Guanidino-3-methylbutyl)-5-isoquinolinesulfonamide [referredto as "Compound (36)"];

(37) N-(4-Guanidino-3-phenylbutyl)-5-isoquinolinesulfonamide [referredto as "Compound (37)"];

(38) N-(5-Guanidino-4-benzylpentyl)-5-isoquinolinesulfonamide [referredto as "Compound (38)"];

(39) N-(5-Guanidino-2-benzylpentyl)-5-isoquinolinesulfonamide [referredto as "Compound (39)"];

(40) N-(b 5-Guanidino-3-phenylpentyl)-5-isoquinolinesulfonamide[referred to as "Compound (40)"];

(41) N-(2-Guanidino-1-methylpropyl)-5-isoquinolinesulfonamide [referredto as "Compound (41)"];

(42) N-(3-Guanidino-1-methylbutyl)-5-isoquinolinesulfonamide [referredto as "Compound (42)"];

(43) N-(6-Guanidino-1-methylheptyl)-5-isoquinolinesulfonamide [referredto as "Compound (43)"];

(44) 4-Amidino-1-(5-isoquinolinesulfonyl)piperazine [referred to as"Compound (44)"];

(45) 4-Amidino-1-(5-isoquinolinesulfonyl)homopiperazine [referred to as"Compound (45)"];

(46) 4-Amidino-1-(5-isoquinolinesulfonyl)-3-methylpiperazine [referredto as "Compound (46)"];

(47) 4-Amidino-1-(5-isoquinolinesulfonyl)-2-methylpiperazine [referredto as "Compound (47)"];

(48) 4-Amidino-1-(5-isoquinolinesulfonyl)-2-isobutylpiperazine [referredto as "Compound (48)"];

(49) 4-Amidino-2,5-dimethyl-1-(5-isoquinolinesulfonyl)piperazine[referred to as "Compound (49)"];

(50) 2-[2-(5-Isoquinolinesulfonamido)ethylaminol]-2-imidazoline[referred to as "Compound (50)"];

(51)2-[2-(5-Isoquinolinesulfonamido)ethylamino]-1,4,5,6-tetrahydropyrimidine[referred to as "Compound (51)"];

(52) N-[2-(3-Methylguanidino)ethyl]-5-isoquinolinesulfonamide [referredto as "Compound (52)"];

(53) N-[2-(2,3-Dimethylguanidino)ethyl]-5-isoquinolinesulfonamide[referred to as "Compound (53)"];

(54) N-[2-(2,3-Diethylguanidino)ethyl]-5-isoquinolinesulfonamide[referred to as "Compound (54"];

(55) N-[2,(3-Ethylguanidino)ethyl]-5-isoquinolinesulfonamide [referredto as "Compound (55)"];

The acid addition salts of the isoquinolinesulfonamide derivatives ofFormula (I) according to this invention are pharmaceutically acceptablenon-toxic salts and can be prepared by conventional methods.

Suitable examples of such pharmaceutically acceptable acid additionsalts include the salts of inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, and sulfuric acid; and the salts oforganic acids such as acetic acid, citric acid, tartaric acid, lacticacid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid andp-toluenesulfonic acid.

The isoquinolinesulfonamide derivatives of Formula (I) of this inventioncan be prepared in accordance with the following equation. ##STR4##wherein A, R₁, R₂, R₃ and R₄ are the same as defined above in Formula(I), R₅ is a halogen atom, R₆ --O-- or R₆ --S-- (R₆ is alkyl group) andY is an acid residue, preferably a pharmaceutically acceptable acidresidue.

Exemplary compounds of Formula (III) include S-methylisothioureasulfate, O-methylisourea sulfate, chloroformamidine hydrochloride,bromoformamidine hydrobromide, S-ethylisothiourea hydrobromide,S-methylisothiourea hydroiodide, O-ethylisourea sulfate,1,2,3-trimethylisourea hydroiodide, 1,2,3-trimethylisothioureahydroiodide, 1,3-dimethyl-2-ethylisothiourea hydroiodide,1,2,3-triethylisothiourea hydroiodide, 2-methylthio-2-imidazolinehydroiodide and 2-methylthio-1,4,5,6-tetrahydropyrimidine. Abovematerial compounds (II) can be prepared by method (A) or method (B) asfollows; ##STR5## wherein A, R₁ and R₂ are the same as defined above, Xis a protective group.

Exemplary compounds of Formula (V) include hydrazine, 1,2-diaminoethane,1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane,1,6-diaminohexane, 1,8-diaminooctane, 1,10-diaminodecane,1,3-diamino-2-phenylpropane, 1,3-diamino-2-benzylpropane,1,5-diamino-3-methylpentane, 2,3-diaminobutane, 2,4-diaminopentane,2,7-diaminooctane, piperazine, homopiperazine, 2-methylpiperazine and2,5-dimethylpiperazine.

Exemplary protective groups of compound of Formula (VI) include formylgroup, acetyl group, benzyl group, benzyloxycarbonyl group andt-butoxycarbonyl group.

Exemplary compounds of Formula (VI) include2-amino-1-benzyloxycarbonylaminopropane,2-amino-1-benzyloxycarbonylaminobutane,2-amino-1-benzyloxycarbonylaminohexane,2-amino-1-benzyloxycarbonylamino-2-phenylethane,2-amino-1-benzyloxycarbonylamino-3-phenylpropane,2-acetamido-1-aminopropane, 2-acetamido-1-amino-3-methylbutane,2-acetamido-1-amino-2-phenylethane, 2-acetamido-1-amino-3-phenylpropane,2-amino-1-formamido-3-phenylpropane,2-amino-1-t-butoxycarbonylamino-3-phenylpropane,1-amino-3-benzamido-3-phenylpropane, 1-acetamido-3-amino-4-phenylbutane,1-amino-3-benzyloxycarbonylamino-1-phenylpropane,1-amino-4-t-butoxycarbonylamino-3-phenylbutane,1-amino-4-t-butoxycarbonylamino-3-methylbutane,1-amino-5-t-butoxycarbonylamino-4-benzylpentane and1-amino-5-t-butoxycarbonylamino-2-benzylpentane.

The reaction between the compound of Formula (IV) and the compound ofFormula (VI) can be carried out in the presence or absence of an acidacceptor. Exemplary acid acceptors which can be employed include alkalimetal compounds such as a hydroxide, bicarbonate, carbonate, hydride oran alkoxide, e.g. sodium bicarbonate, sodium carbonate, potassiumcarbonate, sodium hydroxide, potassium hydroxide, sodium hydride andsodium alkoxides such as sodium methoxide and organic tertiary aminessuch as trimethylamine, triethylamine, triethylenediamine and pyridine.

In general, this reaction is carried out in the presence of a reactionmedium. Exemplary reaction media which can be employed includehalogenated hydrocarbons such as chloroform and dichloromethane;alcohols such as methanol and ethanol; ethers such as tetrahydrofuran,diethylether, dioxane; N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile.

The amount of the compound of Formula (VI) preferably ranges from 1 to10 mols, more preferably from 1 to 3 mol of the compound of Formula (IV)when the acid acceptor is present, and preferably from 2 to 20 mols,more preferably from 2 to 10 mols per mol of the compound of Formula(IV) when the acid acceptor is absent.

The amount of the acid acceptor employed is preferably about 1 to about10 equivalents and more preferably about 1 to about 6 equivalents foreach mol of the compound of Formula (IV).

The reaction between the compound of Formula (IV) and the compound ofFormula (VI) can be carried out typically at a temperature of from about-30° C. to about 150° C. and preferably from about 0° C. to about 120°C. and more preferably from about 0° C. to about 80° C.

The reaction time which can be employed is typically about 0.5 to about72 hours and preferably about 1 to about 5 hours.

The method of obtaining the compound of Formula (II) from the compoundof Formula (VII) may vary depending upon the protective group of Xselected, generally known methods can be employed in this invention. Forexample, when the protective group of X is an acyl group such as formyl,acetyl or benzoyl, the desired compounds can be obtained by hydrolysiswith an acid or an alkali. When the protective group of X is analkyloxycarbonyl group such as tert-butoxycarbonyl, the desired productscan be obtained by hydrolysis with an acid. When the protective group ofX is an arylmethyloxycarbonyl group such as benzyloxycarbonyl, thedesired compounds can be obtained by hydrogenation or hydrolysis with anacid.

The reaction between the compound of Formula (IV) and the compound ofFormula (V) can be carried out under the same condition as the reactionbetween the compound of Formula (IV) and the compound of Formula (VI)except that the amount of the compound of Formula (V) preferably rangesfrom 2 to 10 mols 1 more preferably from 2 to 4 mols per mol thecompound of Formula (IV) when the acid acceptor is present, andpreferably from 3 to 20 mols, more preferably from 3 to 7 mols per molof the compound of Formula (IV) when the acid acceptor is absent.

In general, the reaction between the compound of Formula (II) and thecompound of Formula (III) can be carried out in the presence of an acidacceptor. Exemplary acid acceptors which can be employed include alkalimetal compounds such as a sodium bicarbonate, sodium carbonate,potassium carbonate and sodium hydroxide, organic tertiary amines suchas trimethylamine, triethylamine, triethylenediamine and pyridine.

In general, this reaction is carried out in the presence of a reactionmedium. Exemplary reaction media which can be employed include water andalkanols such as methanol and ethanol, or their mixture with water;mixture of ethers such as tetrahydrofuran and dioxane, and water. Themixture rate (V/V) of water against alkanols of ethers is preferablyfrom 20 percent to 100 percent.

The amount of the acid acceptor employed is preferably about 1 to about10 equivalents and more preferably about 1 to 4 equivalents for each molof the compound of Formula (II) in the reaction between the compound ofFormula (II) and the compound of Formula (III).

The amount of the compound of Formula (III) is at least 1 mol,preferably from 1 to 10 mols, more preferably from 2 to 4 mols per moldof the compound of Formula (II).

The reaction between the compound of Formula (II) and the compound ofFormula (III) can be carried out preferably at a temperature of fromabout 20° C. to about 150° C. and more preferably from about 50° C. toabout 120° C.

The reaction time which can be employed is preferably about 2 to about 6hours.

Also, the compound of Formula (I) can be prepared by the followingequations: ##STR6## wherein A, R₁, R₂, R₃ and R₄ are the same as definedabove in Formula (I).

Exemplary compounds of the Formula (VIII) include 2-guanidinoethylamine,3-guanidinopropylamine, 4-guanidinobutylamine,3-guanidino-2-phenylpropylamine, 6-guanidinohexylamine,1-amidinopiperazine, 1-amidino-2-5-dimethylpiperazine,1-amidino-3-methylpiperazine and 1-amidinohomopiperazine.

The compounds of the Formula (VIII) can be easily prepared fromcorresponding diamine and the compound of the Formula (III). Forexample, 2-guanidinoethylamine can be prepared from 1,2-diaminoethaneand S-methylisothiourea, and 1-amidinopiperadine can be prepared frompiperazine and S-methylisothiourea.

The amount of the compound of Formula (VIII) is at least 1 mol,preferably 1 to about 10 mols per mol of the compound of Formula (IV).

In general, the reaction between the compound of Formula (IV) and thecompound of Formula (VIII) can be carried out in the presence of an acidacceptor. Exemplary acid acceptors which can be employed include alkalimetal compounds such as sodium bicarbonate, sodium carbonate, potassiumcarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodiummethoxide; and organic tertiary amines such as trimethylamine,triethylamine, triethylenediamine and pyridine.

In general, this reaction is carried out in the presence of a reactionmedium. Exemplary reaction media which can be employed include water andalkanols such as methanol and ethanol, or their mixture with water;mixture of ethers such as tetrahydrofuran, dioxane,N,N-dimethylformamide and acetone, and water.

The mixture rate (V/V) of water against alcohols of ethers is preferablyfrom 20 percent to 100 percent.

The amount of the acid acceptor employed is preferably about 1 to about10 equivalents and more preferably about 1 to about 4 equivalents foreach mol of the compound of Formula (IV) in the reaction between thecompound of Formula (IV) and the compound of Formula (VIII).

The reaction between the compound of Formula (IV) and the compound ofFormula (VIII) can be carried out typically at a temperature of fromabout -30° C. to about 150° C., preferably from about -10° C. to about80° C. and more preferably from about 0° C. to about 30° C.

The reaction time which can be employed is typically about 0.5 to about72 hours and preferably about 1 to about 5 hours.

It has now been found that the isoquinolinesulfonamide derivatives ofFormula (I) and the pharmaceutically acceptable salts havepharmacologically and biochemically interesting properites such as arelaxatory action for vascular smooth muscle, an action for increasingblood flow and hypotensive action and are useful as a vasodilator, ahypotensor, an ameliorant of cerebral circulation, a medicine for anginapectoris and a preventive and a medicine for cardiovascular thrombosis.

The effect of the isoquinolinesulfonamide derivatives and thepharmaceutically acceptable acid addition salts of this invention onsmooth muscle can be proved by suspending a mesenteric artery taken outfrom a rabbit in a helical form, contracting the mesenteric artery withpotassium chloride and adding the isoquinolinesulfonyl derivatives ortheir pharmaceutically acceptable acid addition salts of this inventionto the contracted mesenteric artery, resulting in the relaxation of themesenteric artery. When, for example,N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, i.e., compound (2) wasadded and a complete relaxation was designated 100%, the concentrationwhich could bring about a relaxation of 50%, i.e., ED₅₀ was 1 μM.

The effect of the isoquinolinesulfonamide derivatives and thepharmaceutically acceptable acid addition salts of this invention on thevasodilatation of the femoral and vertebral arteries can be measured byanesthetizing a dog of mixed breed weighing 8 to 15 Kg by an intravenousadministration of 35 mg/Kg of pentbarbital, providing an acute typeprobe (a product of Nippon Koden K.K., Japan) with the femoral andvertebral arteries, administering the isoquinolinesulfonamidederivatives and the pharmaceutically acceptable acid addition salts tothe femoral vein through a polyethylene tube inserted into the femoralvein side chain and measuring the blood flow volume with anelectromagnetic flowmeter (a product of Nippon Koden K.K., Japan,"MFV-1200"). 1 mg/Kg of N-(2-guanidinoethyl)-5-isoquinolinesulfonamide,i.e., Compound (2) was intravenously administered, the increased bloodflow volumes in the vertebral artery and in the femoral artery were 95%and 37%. And the duration time is more than 30 minutes.

Furthermore, when another isoquinolinesulfonamide derivatives and thepharmaceutically acceptable acid addition salts of this invention wereintraveneously and arterially administered for the above describedpurposes, remarkable increase of blood flow could be observed. Alsoremarkable and durable hypotensive action could be observed, and bloodpressure of 32 mmHg decreased at advantage of blood pressure. The actioncontinued more than 30 minutes.

When the toxity test of the compound of this invention was done by usingrats and mice, any remarkable toxity against the center, the kidney andthe liver could not be observed.

For example, the acute toxicity ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide i.e., Compound (2) i.e.,LD₅₀ was 59 mg/Kg in giving male ddY-strain mice an intravenousadministration.

The following examples illustrate the present invention in more detail,but they are given for illustrative purposes only and are not to beconstrued as limiting the invention.

REFERENTIAL EXAMPLE 1

In 200 ml of chloroform was dissolved 12.0 g of 1,2-diaminoethane, andto the solution was added dropwise 100 ml of a chloroform solutioncontaining 4.55 g of 5-isoquinolinesulfonyl chloride under cooling withice. After the dropwise addition of the chloroform solution, the mixedsolution was stirred at a temperature of 20° C. to 25° C. for two hours,and then the reaction solution was extracted with a 10% aqueoushydrochloric acid solution. The pH of the aqueous layer was adjusted to10 with a 10% aqueous sodium hydroxide solution, and the aqueous layerwas extracted with chloroform. The chloroform layer extracted was washedwith water and dried with anhydrous potassium carbonate. Then thechloroform was distilled from the chloroform layer, and the residueobtained was subjected to a column chromatography [silica gel: 200 g;developing solvent: 2% methanol/chloroform (volume ratio)] to give 3.3 gof N-(2-aminoethyl)-5-isoquinolinesulfonamide as an oily substace in ayield of 66%.

The same procedures as described above were repeated using the compoundsof Formula (V) as set forth in Table 1 under the reaction conditions asset forth in Table 1, and N-(ω-aminoalkyl)-5-isoquinolinesulfonamide asset forth in Table 1 were obtained.

The equation is as follows; ##STR7##

                                      TABLE 1                                     __________________________________________________________________________     Run                                                                                         Compound of Formula (V)                                                                    TemperatureReaction                                                                  TimeReaction                                                                       ##STR8##                              No.                                                                              (g)        (g)          (°C.)                                                                         (hour)                                                                             n   [g  [(%)]                          __________________________________________________________________________    1  3.41       H.sub.2 N(CH.sub.2).sub.3 NH.sub.2                                                     11.1                                                                              20˜25                                                                          2    3   2.9 (73)                           2  4.55       H.sub.2 N(CH.sub.2).sub.4 NH.sub.2                                                     11.0                                                                              "      2    4   3.46                                                                              (62)                           3  4.55       H.sub.2 N(CH.sub.2).sub.5 NH.sub.2                                                     11.5                                                                              "      3    5   4.16                                                                              (71)                           4  4.55       H.sub.2 N(CH.sub.2).sub.6 NH.sub.2                                                     11.6                                                                              "      5    6   4.6 (75)                           5  4.0        H.sub.2 N(CH.sub.2).sub.8 NH.sub.2                                                     13.0                                                                              "      4    8   3.83                                                                              (65)                           6  2.28       H.sub.2 N(CH.sub.2).sub.10 NH.sub.2                                                    8.62                                                                              "      10   10  2.2 (61)                           __________________________________________________________________________

REFERENTIAL EXAMPLE 2

In 50 ml of a chloroform solution containing 11.55 g of1,3-diamino-2-phenylpropane and 1.33 g of triethylamine was addeddropwise 30 ml of a chloroform solution containing 3.5 g of5-isoquinolinesulfonyl chloride under cooling with ice. After thedropwise addition of the chloroform solution, the mixed solution wasstirred at a temperature of 10° C. to 20° C. for four hours, and thereaction mixture solution was washed with water and dried with anhydrouspotassium carbonate. After the chloroform was distilled therefrom, theresidue thus obtained was subjected to a silica gel columnchromatography (silica gel: 90 g; solvent: 5% methanol/chloroform(volume ratio)) to give 3.20 g ofN-(3-amino-2-phenylpropyl)-5-isoquinolinesulfonamide in a yield of 61%.

The same procedures as described above were repeated using the compoundsof Formula (V) as set forth in Table 2-1 under the reaction conditionsas set forth in Table 2-1, and compounds as set forth in Table 2-2 wereobtained.

The equation is as follows; ##STR9##

                                      TABLE 2                                     __________________________________________________________________________     Run                                                                                         Compound of Formula (V)                                                                     Acid acceptor                                                                        Temper-Reaction                                                                     TimeReaction                                                                       ##STR10##                      No.                                                                              (g)        (g)           (g)    ature (°C.)                                                                  (hour)                                                                             P   R    [g  (%)]               __________________________________________________________________________    1  4.0                                                                                       ##STR11## 6.96                                                                             K.sub.2 CO.sub.3                                                                  6.06                                                                              5˜10                                                                         4    1   CH.sub.3                                                                           3.43                                                                              (70)               2  4.0                                                                                       ##STR12## 11.53                                                                            NEt.sub.3                                                                         7.10                                                                             20˜25                                                                         5    1   CH.sub.2 Ph                                                                        4.17                                                                              (67)               __________________________________________________________________________

REFERENTIAL EXAMPLE 3

In 20 ml of a chloroform solution containing 2.23 g of2-benzyloxycarbonylamino-1-methylethylamine and 1.2 g of triethylaminewas added dropwise 20 ml of a chloroform solution containing 1.80 g of5-isoquinolinesulfonyl chloride under cooling with ice. After thedropwise addition of the chloroform solution, the mixed solution wasstirred at a temperature of 20° C. to 25° C. for two hours, and thereaction mixture solution was washed with water and dried with anhydrousmagnesium sulfate. The chloroform was distilled therefrom under reducedpressure. The crystalline residue thus obtained was recrystallized fromethanol to give 2.68 g ofN-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide ina yield of 85%.

In 50 ml of ethanol was dissolved 2.0 g ofN-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamideobtained above, and to the solution was added 0.1 g of 5%palladium-carbon. Then the solution was stirred at a temperature of 15°C.˜25° C. in a hydrogen (0.7 to 1.40 kg/cm²) for 3 hours. Thepalladium-carbon was separated from the reaction solution by filtrationunder the reduced pressure. After the methanol was distilled therefrom,the reaction solution was concentrated to dryness to give 1.30 g ofN-(2-amino-1-methylethyl)-5-isoquinolinesulfonamide in a yield of 98%.

The same procedures as described above were repeated by using thecompounds of Formula (VI) as set forth in Table 3 under the reactionconditions as set forth in Table 3 and 4, and compounds as set forth inTable 3 and 4 were obtained.

The equation is as follows; ##STR13## wherein Z represents ##STR14##

                                      TABLE 3                                     __________________________________________________________________________     Run                                                                                              ##STR15##                                                                              NEt.sub.3                                                                        TemperatureReaction                                                                  TimeReaction                                                                       ##STR16##                         No.                                                                              (g)        R    (g)      (g)                                                                              (°C.)                                                                         (hour)                                                                             [g     (%)]                        __________________________________________________________________________    1  4.0        Et   4.28     2.13                                                                             20˜25                                                                          3    6.38   (88)                        2  3.5        n-Bu 4.61     2.02                                                                             20˜25                                                                          2    5.89   (87)                        3  3.0        Ph   3.91     1.73                                                                              0˜10                                                                          4    5.10   (84)                        4  3.0        CH.sub.2 Ph                                                                        4.4      1.86                                                                              0˜10                                                                          5    5.56   (89)                        __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     Run                                                                              ##STR17##     5% Pd/C                                                                            TemperatureReaction                                                                  TimeReaction                                                                       ##STR18##                                  No.                                                                              R      (g)    (g)  (°C.)                                                                         (hour)                                                                             [g     (%)]                                 __________________________________________________________________________    1  Et     5.0    0.1  20˜25                                                                          4    3.34   (99)                                 2  n-Bu   "      "    "      3    3.41   (98)                                 3  Ph     "      "    "      2    3.44   (97)                                 4  CH.sub.2 Ph                                                                          "      "    "      2    3.52   (98)                                 __________________________________________________________________________

REFERENTIAL EXAMPLE 4

In 50 ml of a chloroform solution containing 2.0 g of2-acetylaminopropylamine and 2.6 g of triethylamine was added dropwise50 ml of a chloroform solution containing 3.28 g of5-isoquinolinesulfonyl chloride under cooling with ice. The mixedsolution was stirred at a temperature of 15° C. to 25° C. for two hours,and then the reaction solution was washed with water and dried withanhydrous sodium sulfate. The chloroform was distilled therefrom underreduced pressure. The crystalline residue thus obtained wasrecrystallized from methanol to give 3.67 g ofN-(2-acetylaminopropyl)-5-isoquinolinesulfonamide in a yield of 83%.

In 50 ml of 10% hydrochloride was dissolved 3.0 g ofN-(2-acetylaminopropyl)-5-isoquinolinesulfonamide as obtained above, andthe mixture was stirred at a temperature of 90° C. to 100° C. for 36hours. The reaction solution was washed with chloroform, renderedalkaline with 1N sodium hydroxide and extracted with chloroform. Thechloroform layer was washed with water, dried with anhydrous magnesiumsulfate, and the chloroform was distilled threfrom under reducedpressure. The residue thus obtained was subjected to an alumina columnchromatography (alumina: 70 g; solvent: chloroform) to give 1.44 g ofN-(2-aminopropyl)-5-isoquinolinesulfonamide in a yield of 56%.

The same procedures as described above were repeated using the compoundsFormula (IV) as set forth in Table 5 under the reaction conditions asset forth in Table 5 and 6, and there were obtainedN-(2-amino-3-methylbutyl)-5-isoquinolinesulfonamide,N-(2-amino-2-phenylethyl)-5-isoquinolinesulfonamide andN-(2-amino-3-phenylpropyl)-5-isoquinolinesulfonamide.

The equation is as follows; ##STR19##

                                      TABLE 5                                     __________________________________________________________________________     Run                                                                                         ##STR20##   Et.sub.3 N                                                                       TemperatureReaction                                                                  TimeReaction                                                                       ##STR21##                           No.                                                                              (g)        R     (g)   (g)                                                                              (°C.)                                                                         (hour)                                                                             [g      (%)]                         __________________________________________________________________________    1  4.0        i-Pr  2.8   2.66                                                                             20˜25                                                                          2    5.19    (88)                         2  "          Ph    3.75  "  10˜20                                                                          "    5.83    (90)                         3  "          PhCH.sub.2                                                                          4.04  "  10˜20                                                                          "    5.64    (84)                         __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________     Run                                                                              ##STR22##       of HClConcentration                                                                  TemperatureReaction                                                                  TimeReaction                                                                       ##STR23##                              No.                                                                              R       (g)     (ml)   (°C.)                                                                         (hour)                                                                             [g     (g)]                             __________________________________________________________________________    1  iPr     5.0     10%    90˜100                                                                         24   2.63   (60)                                                (70)                                                       2  Ph      "       10%    "      "    2.92   (66)                                                (70)                                                       3  PhCH.sub.2                                                                            "       10%    "      "    2.23   (50)                                                (70)                                                       __________________________________________________________________________

REFERENTIAL EXAMPLE 5

The same procedure as described in Referential example 3 were repeatedusing 4.0 g of 5-isoquinolinesulfonyl chloride, 6.95 g of4-t-butoxycarbonylamino-3-phenylbutylamine and 2.66 g of triethylamine,and there were obtained 6.6 g ofN-(4-t-butoxycarbonylamino-3-phenylbutyl)-5-isoquinolinesulfonamide in ayield of 83%.

In 30 ml of trifluoroacetic acid was dissolved 6.0 g ofN-(4-t-butoxycarbonylamino-3-phenylbutyl)-5-isoquinolinesulfonamide, andleft at a temperature of 20° C.˜25° C. for 30 minutes. The mixrure wascondensed under reduced pressure. To the reaction solution was addedethyl ether, and the crystals precipitated were separated by filtration.The crystals thus obtained were washed with ethylether to give 4.54 g ofN-(4-amino-3-phenylbutyl)-5-isoquinolinesulfonamide in a yield of 97%.

The same procedures as described above were repeated using the compoundsof Formula (VI) as set forth in Table 7 under the reaction conditions asset in Table 7 and 8, and there were obtainedN-(4-amino-3-methylbutyl)-5-isoquinolinesulfonamide,N-(5-amino-4-benzylpentyl)-5-isoquinolinesulfonamide andN-(5-amino-2-benzypentyl)-5-isoquinolinesulfonamide.

The equation is as follows; ##STR24##

                                      TABLE 7                                     __________________________________________________________________________     Run                                                                                            ##STR25##        NEt.sub.3                                                                        ReactionTemperature                                                          (°C.)Reaction                                                                    YieldFormula (VII)Compound                                                   of                              No.                                                                              (g)           q     R    (g)   (g)                                                                              Time (hour)                                                                            [g  (%)]                        __________________________________________________________________________    1  3.0           2     CH.sub.3                                                                           3.47  2.0                                                                              20˜25                                                                            4.55                                                                              (88)                                         1                   2                                        2  "             3     PhCH.sub.2                                                                         4.63  "  20˜25                                                                            5.34                                                                              (84)                                         1                   2                                        3  "             1     PhCH.sub.2                                                                         4.63  "  20˜25                                                                            5.53                                                                              (87)                                         3                   2                                        __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________     ##STR26##                                                                                                                  ##STR27##                       (VII)                                        (II)                             p                          Reaction Temper-                                                                        Reaction                                                                              Yield                            Run No.                                                                             q       R   (g)      ature (°C.)                                                                      Time (Min.)                                                                           [g       (%)]                    __________________________________________________________________________    1     2       CH.sub.3                                                                          4        20˜25                                                                             30      2.96     (99)                          1                                                                       2     3       PhCH.sub.2                                                                        5        "         "       3.43     (87)                          1                                                                       3     1       PhCH.sub.2                                                                        5        "         "       3.73     (94)                          3                                                                       __________________________________________________________________________

REFERENTIAL EXAMPLE 6

In 100 ml of chloroform was dissolved 12.9 g of 2,3-diaminobutane and tothe solution was added dropwise 10 ml of a chloroform solutioncontaining 4.0 g of 5-isoquinolinesulfonyl chloride under cooling withice. After the dropwise addition of the chloroform solution, the mixedsolution was stirred at a temperature of 20° C. to 25° C. for two hours,and the reaction mixture solution was washed with water and dried withanhydrous sodium carbonate. The chloroform was distilled therefrom underreduced pressure, and the residue thus obtained was subjected to acolumn chromatography [silica gel: 160 g; solvent: chloroform] to give3.92 g of N-(2-amino-1-methylpropyl)-5-isoquinolinesulfonamide in ayield of 80%.

The same procedures as described above were repeated using the compoundsof Formula (V) as set forth in Table 9 under the reaction conditions asset forth in Table 9, andN-(6-amino-1-methylheptyl)-5-isoquinolinesulfonamide were obtained.

The equation is as follows; ##STR28##

                                      TABLE 9                                     __________________________________________________________________________                 ##STR29##    Reaction Temper-                                                                                    ##STR30##                     (g)         (g)          ature (°C.)                                                                      Reaction Time (hour)                                                                      [g      (%)]                   __________________________________________________________________________    4           16.8         20˜25                                                                             3           5.24    (89)                   __________________________________________________________________________

EXAMPLE 1

In 30 ml of methanol was dissolved 3.3 g ofN-(2-aminoethyl)-5-isoquinolinesulfonamide obtained in Referentialexample 1, and to the solution was added 25 ml of water solutioncontaining 5.0 g of S-methylisothiourea sulfate. And to the mixedsolution was added 1N aqueous sodium hydroxide solution, the mixedsolution thus obtained was heated at reflux for two hours. After thereflux, the methanol was distilled therefrom under reduced pressure, andthe white crystals precipitated were separated by filtration underreduced pressure. The crystalline residue thus obtained wasrecrystallized from methanol to give 3.24 g ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide, i.e., Compound (2) in ayield of 84%.

Mass spectrum (m/e): 294 (M+1), 235, 207, 192 and 128.

NMR spectrum (D₂ O), DCl, δ): 3.0˜3.3 (4H, 2×CH₂), 8.0˜8.3 (1H), 8.7˜9.1(4H) and 9.9 (1H).

IR absorption spectrum (ν_(max), cm⁻¹): 3300, 3500, 1690, 1650, 1200 and1170.

The same procedures as described above were repeated using the compoundsof Formula (II) and the compounds of Formula (III) as set forth in Table10 under the reaction conditions as set forth in Table 10, and therewere obtained N-(ω-guanidinoalkyl)-5-isoquinolinesulfonamide as setforth in Table 11.

The equation is as follows; ##STR31##

                                      TABLE 10                                    __________________________________________________________________________                       ##STR32##                                                  (II)              (III)                         Reaction                                                                             Reflax                 Run No.                                                                             n     (g)   (g)          Acid acceptor (g)                                                                      Solvent Temperature                                                                          Time                   __________________________________________________________________________                                                           (hour)                 1     3     1.0                                                                                  ##STR33##   NaOH 0.453                                                                             H.sub.2 O                                                                             Reflux 3                                        1.44                                                        2     4     "                                                                                    ##STR34##   K.sub.2 CO.sub.3 0.98                                                                  MeOH:H.sub.2 O 60:40                                                                  "      4                                        1.14                                                        3     5     "                                                                                    ##STR35##   K.sub.2 CO.sub.3 0.82                                                                  MeOH:H.sub.2 O 60:40                                                                  "      4                                        1.63                                                        4     6     "                                                                                    ##STR36##   K.sub.2 CO.sub.3 0.79                                                                  EtOH:H.sub.2 O 50:50                                                                  "      4                                        1.45                                                        5     8     "                                                                                    ##STR37##   K.sub.2 CO.sub.3 0.62                                                                  EtOH:H.sub.2 O 70:30                                                                  "      3                                        1.52                                                        6     10    "                                                                                    ##STR38##   K.sub.2 CO.sub.3 0.69                                                                  EtOH:H.sub.2 O 80:20                                                                  "      3                                        1.26                                                        __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________                   ##STR39##                 IR Absorp-                                              Yield                tion Spectrum                         Run No.                                                                             Compound No.                                                                          n    [g   (%)] Mass Spectrum (m/e)                                                                      (.sup.ν max,                                                                       NMR Spectrum (D.sub.2 O,                                                      DCl, δ)                 __________________________________________________________________________    1     3       3    1.04 (90) 308        1690, 1640                                                                            1.5˜1.7 (2H),                                                           3.0˜3.3                                              235, 192   1200, 1170                                                                            (4H), 8.7˜9.1                                                           (4H),                                                                         9.9 (1H), 8.0˜8.3                                                       (1H)                          2     4       4    1.03 (89) 322, 277   1680, 1640                                                                            1.4˜1.7 (4H),                                                           3.0˜3.3                                              235, 221   1200, 1160                                                                            (4H), 8.7˜9.1                                                           (4H),                                                      207, 192   1050    9.9 (1H), 8.0˜8.3                                                       (1H)                          3     5       5    1.05 (92) 336, 263, 249                                                                            1690, 1630                                                                            1.4˜1.7 (6H),                                                           3.0˜3.3                                              235, 221, 207                                                                            1200, 1160                                                                            (4H), 8.7˜9.1                                                           (4H),                                                      192        1070    9.9 (1H), 8.0˜8.3                                                       (1H)                          4     6       6    0.989                                                                              (87) 350, 290, 249                                                                            1690, 1640                                                                            1.3˜1.7 (8H),                                                           3.0˜3.3                                              235, 207, 192                                                                            1200, 1180                                                                            (4H), 8.0˜8.3                                                           (1H),                                                                 1070    8.7˜9.1 (4H), 9.9                                                       (1H)                          5     7       8    0.923                                                                              (82) 378        1680, 1630                                                                            1.3˜1.7 (12H),                                                          3.0˜3.3                                              319, 277, 235                                                                            1200, 1170                                                                            (4H), 8.0˜8.3 (1H),                                                     8.7˜                                                 207, 192           9.1 (4H), 9.9 (1H)            6     8       10   0.881                                                                              (79) 406, 333, 305                                                                            1700, 1650                                                                            1.3˜1.7 (16H),                                                          3.0˜3.3                                              235, 221, 207                                                                            1200, 1170                                                                            (4H), 8.0˜8.3 (1H),                                                     8.7˜                                                 192                9.1 (4H), 9.9                 __________________________________________________________________________                                                    (1H)                      

EXAMPLE 2

The mixture solution of 20 ml of water and 40 ml of 2N-sodium hydroxide,containing 5.02 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide obtainedin Referential example 1 and 7.38 g of O-methylisourea sulfate wasstirred at a temperature of 80° C. for three hours. After the reactionsolution was cooled with ice, the pH of the aqueous layer was adjustedto 11 with a 2N aqueous sodium hydroxide solution. The white crystalsprecipitated were separated by filtration, and to the residue thusobtained was added 10 ml of a 2N aqueous hydrochloric acid solution. ThepH of the solution was adjusted to 11 with a 2N aqueous sodium hydroxidesolution. The crystals precipitated were separated by filtration, thecrystalline residue thus obtained was washed with water and condensed todryness to give 2.65 g ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide, i.e., Compound (2) in ayield of 90%.

EXAMPLE 3

In 20 ml of a tetrahydrofuran solution containing 1.64 g of5-isoquinolinesulfonyl chloride was added dropwise 0.9 ml of a 80%hydrazine hydrate under cooling with ice. After the dropwise addition ofa hydrazine hydrate, the mixed solution obtained was stirred undercooling with ice for 1 hour. The crystals precipitated were separated,and the crystalline residue was washed with water and tetrahydrofuran.To the residue obtained was added 5 ml of methanol and 2 ml of water,and the pH of the aqueous layer was adjusted to 2 with 10% hydrochloricacid. After the methanol was distilled therefrom the crystalline residuethus obtained was recrystallized from water and methanol solution togive 1.26 g of 5-isoquinolinesulfonohydrazine in a yield of 78%.

In 20 ml of 0.5N sodium hydroxide was dissolved 1.0 g of5-isoquinolinesulfonohydrazine obtained above and 1.53 g ofS-methylisothiourea sulfate, and the mixture solution was heated atreflux for 1 hour. The sodium hydroxide was distilled under reducedpressure and to the residue thus obtained was added a 10 ml of methanol.The insoluble part was removed by filtration. After the methanol wasdistilled from the methanol solution, the crystalline residue thusobtained was recrystallized from methanol/ethanol to give 0.72 g ofN-guanidino-5-isoquinolinesulfonamide, i.e., Compound (1) in a yield of64%.

NMR spectrum (DMSO-d₆, δ): 7.3˜8.4 (4H), 8.5 (2H) and 9.3 (1H).

IR absorption spectrum (ν_(max), cm⁻¹): 3420, 1680 and 1010.

EXAMPLE 4

In 30 ml of a 60% methanol/water solution (volume ratio) was dissolved 2g of N-(3-amino-2-phenylpropyl)-5-isoquinolinesulfonamide obtainedReferential example 2, 2.05 g of S-methylisothiourea sulfate and 1.67 gof potassium carbonate, and the mixed solution was heated at reflux fortwo hours. After the reflux, the methanol was distilled therefrom underreduced pressure and the white crystalline residue the obtained wasseparated by filtration under reduced pressure. The residue wasrecrystallized from methanol to give 1.93 g ofN-(3-guanidino-2-phenylpropyl)-5-isoquinolinesulfonamide, i.e., Compound(31) in a yield of 86%.

Mass spectrum (m/e): 384, 325, 311 and 207.

NMR spectrum (D₂ O, DCl, δ): 2.2˜2.4 (1H), 3.0˜3.3 (4H), 7.2 (5H),8.0˜8.3 (1H), 8.7˜9.1 (4H) and 9.9 (1H).

IR absorption spectrum (ν_(max), cm⁻¹): 3500, 3300, 1700, 1650, 1200,1180 and 1040.

The same procedures as described above were repeated using the compoundsof Formula (II) as set forth in Table 12 under the reaction conditionsas set forth in Table 12, and there were obtainedN-(3-guanidino-2-methylpropyl)-5-isoquinolinesulfonamide, i.e., Compound(28) and N-(3-guanidino-2-benzylpropyl)-5-isoquinolinesulfonamide, i.e.,Compound (34) as set forth in Table 13.

The equation is as follows; ##STR40##

                                      TABLE 12                                    __________________________________________________________________________     Run                                                                                               Formula (III)Compound of                                                                   Acid acceptor                                                                        TemperatureReaction                                                                  Time Reaction                 No.                                                                              P, R   (g)       (g)    Solvent                                                                             (g)    (°C.)                                                                         (hour)                         __________________________________________________________________________    1  1, CH.sub.3                                                                          1.0       1.43   H.sub.2 O                                                                           K.sub.2 CO.sub.3                                                                     Reflux 2                                                               1.11                                         2  1, CH.sub.2 Ph                                                                       1.0       1.0    EtOH:H.sub.2 O                                                                      K.sub.2 CO.sub.3                                                                     Reflux 3                                                         40:60 0.894                                        __________________________________________________________________________

                                      TABLE 13                                    __________________________________________________________________________              ##STR41##           Mass                                                                               AbsorptionIR                               Run                                                                              Compound       Yield      Spectrum                                                                           Spectrum                                                                             NMR Spectrum                         No.                                                                              No.   n, R     [g   (%)]  (m/e)                                                                              (ν.sub.max, cm.sup.-1)                                                            (D.sub.2 O, DCl,                     __________________________________________________________________________                                             δ)                             1  28    1, CH.sub.3                                                                            1.09 (95)  322, 249                                                                           1690, 1650                                                                           0.9˜1.1 (3H),                                                           2.0˜2.2                                                     235, 207                                                                           1200, 1170                                                                           (1H), 3.0˜3.3 (4H),                                              1030   8.0˜8.3 (1H),                                                           8.7˜9.1                                                                 (4H), 9.9 (1H)                       2  34    1, CH.sub.2 Ph                                                                         1.01 (90)  398, 320                                                                           1680, 1650                                                                           2.0˜2.4 (3H),                                                           3.0˜3.3                                                     307, 221,                                                                          1200, 1170                                                                           (4H), 7.2 (5H), 8.0˜8.3                                     207  1030   (1H), 8.7˜9.1 (4H),                                                     9.9 (1H)                             __________________________________________________________________________

EXAMPLE 5

In 30 ml of a 60% methanol/water solution (volume ratio) was dissolved1.0 g of N-(2-amino-1-methylethyl)-5-isoquinolinesulfonamide obtained inReferential example 3, 1.44 g of S-methylisothiourea sulfate and 0.528 gof sodium hydroxide, and the mixed solution was heated at reflux for thethree hours. After the reflux, the methanol was distilled therefromunder reduced pressure, and to the reaction solution was added water sothat the total volume of the solution was 30 ml. The white crystallineresidue thus obtained was separated by filtration. The residue wasrecrystallized from methanol to give 0.95 g ofN-(2-guanidino-1-methylethyl)-5-isoquinolinesulfonamide, i.e., Compound(9) in a yield of 82%.

Mass spectrum (m/e): 308, 235, 207, 192 and 128.

NMR spectrum (D₂ O, DCl, δ): 1.3˜1.5 (3H), 3.0˜3.3 (3H), 8.0˜8.3 (1H),8.7˜9.1 (4H) and 9.9 (1H).

IR spectrum (ν_(max), cm⁻¹): 3500, 3300, 1690, 1630, 1360, 1180 and1140.

The same procedure as described above were repeated using the compoundsof Formula (II) as set forth in Table 14 under the reaction conditionsas set forth in Table 14, and there were obtainedN-[1-guanidinomethyl)propyl]-5-isoquinolinesulfonamide, i.e., Compound(10), N-[(1-guanidinomethyl)pentyl -5-isoquinolinesulfonamide, i.e.,Compound (13), N-(2-guanidino-1-phenylethyl)-5-isoquinolinesulfonamide,i.e., Compound (23) andN-(2-guanidino-1-benzylethyl)-5-isoquinolinesulfonamide, i.e., Compound(24) as set forth in Table 15.

The equation is as follows; ##STR42##

                                      TABLE 14                                    __________________________________________________________________________     Run                                                                                          Formula (III)Compound of                                                                    Reaction                                                                             TimeReaction                             No.                                                                              R   (g)     (g)    Solvent                                                                              Temperature                                                                          (hour)                                    __________________________________________________________________________    1  Et  3.0     3.69   MeOH:H.sub.2 O                                                                       Reflux 2                                                               40:60                                                   2  n-Bu                                                                              3.0     3.95   MeOH:H.sub.2 O                                                                       Reflux 3                                                               40:60                                                   3  Ph  3.0     2.66   MeOH:H.sub.2 O                                                                       Reflux 3                                                               70:30                                                   4  PhCH.sub.2                                                                        3.0     4.10   MeOH:H.sub.2 O                                                                       Reflux 3                                                               70:30                                                   __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________              ##STR43##       Mass                                                                               AbsorptionIR                                   Run                                                                              Compound      Yield   Spectrum                                                                           Spectrum                                                                             NMR Spectrum                             No.                                                                              No.   R       [g (%)] (m/e)                                                                              (ν.sub.max, cm.sup.-1)                                                            (D.sub.2 O, DCl, δ)                __________________________________________________________________________    1  10    Et      2.93 (85)                                                                             322  1690, 1640                                                                           1.0˜1.2 (3H), 1.6˜2.0                                 249, 207                                                                           1210, 1170                                                                           (2H), 3.0˜3.3 (3H),                                         192  1040   8.0˜8.3 (1H), 8.7˜9.1                                             (4H), 9.9 (1H)                           2  13    n-Bu    3.00 (88)                                                                             350  1700, 1640                                                                           0.9˜1.1 (3H), 1.2˜1.8                                 277, 207                                                                           1210, 1170                                                                           (6H), 3.0˜3.3 (3H),                                         192  1040   8.0˜8.3 (1H), 8.7˜9.1                                             (4H), 9.9 (1H)                           3  23    Ph      2.74 (81)                                                                             370  1710, 1660                                                                           3.0˜3.4 (3H), 7.2 (5H),                                     311, 297                                                                           1210, 1180                                                                           8.0˜8.3 (1H), 8.7˜9.1                                 207, 192                                                                           1040   (4H), 9.9 (1H)                           4  24    PhCH.sub.2                                                                            3.03 (90)                                                                             384, 325                                                                           1700, 1640                                                                           2.1˜2.3 (2H), 3.0˜3.3                                 311, 297                                                                           1200, 1170                                                                           (3H), 7.2 (5H), 8.0˜8.3                                     207, 192                                                                           1040   (1H), 8.7˜9.1 (4H),                                                     9.9 (1H)                                 __________________________________________________________________________

EXAMPLE 6

The same procedures as described in Example 4 were repeated using 1 g ofN-(2-aminopropyl)-5-isoquinolinesulfonamide obtained in Referentialexample 4, 0.56 g sodium hydroxide and 1.52 g of S-methylisothioureasulfate to give 1.05 g ofN-(2-guanidinopropyl)-5-isoquinolinesulfonamide, i.e., Compound (16) ina yield of 90%.

Mass spectrum (m/e): 308, 249, 207, 192 and 128.

NMR spectrum (D₂ O, DCl, δ): 1.3˜1.5 (3H), 3.0˜3.3 (3H), 8.0˜8.3 (1H),8.7˜9.1 (4H) and 9.9 (1H).

IR absorption spectrum (ν_(max), cm⁻¹): 3500, 3300, 1690, 1640, 1200,1180 and 1030.

The same procedures as described above were repeated using the compoundsof Formula (II) as set forth in Table 16 under the reaction conditionsas set forth in Table 16, and there were obtainedN-(2-guanidino-3-methylbutyl)-5-isoquinolinesulfonamide, i.e., Compound(19), N-(2-guanidino-2-phenylethyl)-5-isoquinolinesulfonamide, i.e.,Compound (25) andN-(2-guanidino-3-phenylpropyl)-5-isoquinolinesulfonamide, i.e., Compound(26) as set forth in Table 17.

The equation is as follows: ##STR44##

                                      TABLE 16                                    __________________________________________________________________________     Run                                                                                            ##STR45##    acceptor Acid                                                                            TimeReaction                                                                       Reaction                       No.                                                                              R       (g)   (g)         (g)  Solvent                                                                              (hour)                                                                             Temperature                     __________________________________________________________________________    1  i-Pr    2.5                                                                                  ##STR46##  K.sub.2 CO.sub.3 2.12                                                              MeOH:H.sub.2 O 30:70                                                                 3    Reflux                          2  ph      3.0                                                                                  ##STR47##  NaOH 2.01                                                                          H.sub.2 O                                                                            4    "                               3  PhCH.sub.2                                                                            2.5                                                                                  ##STR48##  NaOH 1.08                                                                          Dioxan:H.sub.2 O 30:70                                                               4    "                               __________________________________________________________________________

                                      TABLE 17                                    __________________________________________________________________________              ##STR49##       Mass                                                                               AbsorptionIR                                   Run                                                                              Compound      Yield   Spectrum                                                                           Spectrum                                                                             NMR Spectrum                             No.                                                                              No.   R       [g (%)] (m/e)                                                                              (ν.sub.max, cm.sup.-1)                                                            (D.sub.2 O, DCl, δ)                __________________________________________________________________________    1  19    i-Pr    2.29 (80)                                                                             336, 277                                                                           1690, 1640                                                                           1.0˜1.2 (6H), 2.0˜2.3                                 235, 207                                                                           1200, 1170                                                                           (1H), 3.0˜3.3 (3H),                                         192, 128                                                                           1040   8.0˜8.3 (1H), 8.7˜9.1                                             (4H), 9.9 (1H)                           2  25    Ph      2.88 (85)                                                                             370, 311                                                                           1700, 1640                                                                           3.0˜3.4 (3H), 7.2 (5H),                                     207, 192                                                                           1200, 1170                                                                           8.0˜8.3 (1H), 8.7˜9.1                                 128  1040   (4H), 9.9 (1H)                           3  26    PhCH.sub.2                                                                            2.27 (81)                                                                             384, 325                                                                           1690, 1640                                                                           2.2˜2.4 (2H), 3.0˜3.3                                 207, 192                                                                           1210, 1170                                                                           (3H), 7.2 (5H), 8.0˜8.3                                     128  1050   (1H), 8.7˜9.1 (4H),                                                     9.9 (1H)                                 __________________________________________________________________________

EXAMPLE 7

The same procedure as described in Example 4 were repeated using 4.0 gof N-(4-amino-3-phenylbutyl)-5-isoquinolinesulfonamide obtained inReferential example 5, 4.29 g of S-methylisothiourea sulfate and 2.5 gof potassium carbonate to give 3.89 g ofN-(4-guanidio-3-phenylbutyl)-5-isoquinolinesulfonamide, i.e., Compound(37) in a yield of 87%.

Mass spectrum (m/e): 398, 325, 207, 192 and 128.

NMR spectrum (D₂ O, DCl, δ): 2.8˜3.3 (5H), 1.7˜1.9 (2H), 7.2 (5H),8.0˜8.3 (1H), 8.7˜9.1 (4H) and 9.9 (1H).

IR absorption spectrum (ν_(max), cm⁻¹): 1700, 1640, 1180, 1160 and 1030.

The same procedures as described above were repeated using the compoundsof Formula (II) as set forth in Table 18 under the reaction conditionsas set forth in Table 18, and there were obtainedN-(4-guanidino-3-methylbutyl)-5-isoquinolinesulfonamide, i.e., Compound(36), N-(5-guanidino-4-benzylpentyl)-5-isoquinolinesulfonamide, i.e.,Compound (38), N-(5-guanidino-2-benzylpentyl)-5-isoquinolinesulfonamide,i.e., Compound (39) as set forth in Table 19.

The equation is as follows; ##STR50##

                                      TABLE 18                                    __________________________________________________________________________                          Compound of            Reaction                         Run                                                                              P                Formula (III)                                                                        K.sub.2 CO.sub.3                                                                        Reaction                                                                             Time                              No.                                                                              q    R     (g)   (g)    (g) Solvent                                                                             Temperature                                                                          (hour)                            __________________________________________________________________________    1  2    CH.sub.3                                                                            2.5   3.79   2.4 H.sub.2 O                                                                           100° C.                                                                       3                                    1                                                                          2  3    PhCH.sub.2                                                                          3.0   3.48   2.16                                                                              EtOH:H.sub.2 O                                                                      Reflux 4                                    1                           70:30                                          3  1    PhCH.sub.2                                                                          3.0   3.48   2.16                                                                              EtOH:H.sub.2 O                                                                      Reflux 4                                    3                           70:30                                          __________________________________________________________________________

                                      TABLE 19                                    __________________________________________________________________________              ##STR51##       Mass                                                                               AbsorptionIR                                   Run                                                                              Compound                                                                            P       Yield   Spectrum                                                                           Spectrum                                                                             NMR Spectrum                             No.                                                                              No.   q  R    [g  (%)]                                                                              (m/e)                                                                              (ν.sub.max, cm.sup.-1)                                                            (D.sub.2 O, DCL, δ)                __________________________________________________________________________    1  36    2  CH.sub.3                                                                           2.57                                                                              (90)                                                                              336  1680, 1620                                                                           1.0˜1.2 (3H), 1.6˜2.2                 1               263,207                                                                            1190, 1160                                                                           (3H), 3.0˜3.3 (4H),                                         192, 128                                                                           1030   8.0˜8.3 (1H), 8.7˜9.1                                             (4H), 9.9 (1H)                           2  38    3  PhCH.sub.2                                                                         2.93                                                                              (88)                                                                              426  1690, 1630                                                                           1.2˜1.5 (2H), 1.6˜2.0                 1               353, 207                                                                           1200, 1170                                                                           (3H), 2.1˜2.3 (2H),                                         192, 128                                                                           1140   3.0˜3.3 (4H), 7.2 (5H),                                                 8.0˜8.3 (1H), 8.7˜9.1                                             (4H), 9.9 (1H)                           3  39    1  PhCH.sub.2                                                                         2.96                                                                              (89)                                                                              426  1690, 1630                                                                           1.2˜1.5 (2H), 1.6˜2.3                 3               325, 207                                                                           1340, 1170                                                                           (5H), 3.0˜3.3 (4H),                                         192, 128                                                                           1140   7.2 (5H), 8.0˜8.3 (1H),                                                 8.7˜9.1 (4H), 9.9                  __________________________________________________________________________                                         (1H)                                 

EXAMPLE 8

In 15 ml of water were suspended 3.0 g ofN-(2-amino-1-methylpropyl)-5-isoquinolinesulfonamide obtained inReferential example 6, 4.48 g of S-methylisothiourea sulfate and 2.30 gof potassium carbonate, and the suspension was heated at reflux for twohours. The reaction mixture solution was cooled to 25° C., and thecrystals precipitated were separated by filtration. The crystallineresidue thus obtained was recrystallized from methanol to give 2.73 g ofN-(2-guanidino-1-methylpropyl)-5-isoquinolinesulfonamide, i.e. Compound(41) in a yield of 79%.

Mass spectrum (m/e): 322, 263, 235, 207 and 128.

NMR spectrum (D₂ O, DCl, δ): 1.1˜1.4 (6H), 3.2˜3.5 (2H), 8.0˜8.3 (1H),8.7˜9.1 (4H) and 9.9 (1H).

IR absorption spectrum (ν_(max), cm⁻¹): 1680, 1640, 1200 and 1180.

The same procedures as described above were repeated using the compoundsof Formula (II) as set forth in Table 20-1 under the reaction conditionsas set forth in Table 20-1, and there were obtainedN-(6-guanidino-1-methylheptyl)-5-isoquinolinesulfonamide, i.e., Compound(43) as set forth in Table 20-2.

The equation is as follows: ##STR52##

                                      TABLE 20                                    __________________________________________________________________________    Compound of                                                                            Compound of             Reaction                                     Formula (II)                                                                           Formula (III)                                                                          K.sub.2 CO.sub.3                                                                    Reaction Time                                         (g)      (g)      (g)   Temperature                                                                            (hour)                                       __________________________________________________________________________    3        3.8      2.01  Reflux   3                                            __________________________________________________________________________                        Mass                                                                               AbsorptionIR                                         Yield              Spectrum                                                                           Spectrum                                                                             NMR Spectrum                                   [g       (%)]      (m/e)                                                                              (ν.sub.max, cm.sup.-1)                                                            (D.sub.2 O, DCl,δ)                       __________________________________________________________________________    2.98     (88)      378, 319                                                                           3350, 3200                                                                           1.1˜1.8 (14H), 3.1˜                                   235, 207                                                                           1680, 1640                                                                           3.5 (2H), 8.0˜8.3                                           192, 128                                                                           1210, 1190                                                                           (1H), 8.7˜9.1 (4H),                                                     9.9 (1H)                                       __________________________________________________________________________

EXAMPLE 9

In 30 ml of water was dissolved 3.9 g of 1-amidinopiperazine sulfate,and 60 ml of tetrahydrofuran solution containing 4.1 g of5-isoquinolinesulfonyl chloride and 1N sodium hydroxide was addeddropwise under cooling with ice so that the pH of the solution maintainthe range from 8 to 8.5. After the dropwise addition, the mixturesolution was stirred for one hour. The crystalline residue wasdiscarded, and the pH of the aqueous layer was adjusted to 1 with anaqueous diluted hydrochloric acid solution. The crystalline residue wasdiscarded, and the pH of the aqueous layer was adjusted to 13 with a 5Naqueous sodium hydroxide solution. The crystals precipitated wereseparated by filtration, and the crystalline residue obtained wasdissolved with an aqueous diluted hydrochloric acid solution. The pH ofthe solution was adjusted to 13.5 with a 2N aqueous sodium hydroxidesolution. The crystals precipitated were separated by filtration, thecrystalline residue was washed with water, methanol and ethylether andcondensed to dryness to give 4.84 g of4-amidino-1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (44) in ayield of 84%.

Mass spectrum (m/e): 319, 302, 278 and 221.

NMR spectrum (DMSO-d₆,D₂ SO₄): 2.6˜3.7 (8H), 7.7˜8.3 (1H), 8.4˜8.9 (4H)and 9.8 (1H).

IR spectrum (.sup.ν max, cm⁻¹): 3320, 1675, 1590, and 1170.

The same procedures as described above were repeated using the compoundsof Formula (VIII) as set forth in Table 21 under the reaction conditionsas set forth in Table 21, and there were obtained4-amidino-1-(5-isoquinolinesulfonyl)homopiperazine, i.e., Compound (45),4-amidino-1-(5-isoquinolinesulfonyl)-2-methylpiperazine, i.e., Compound(47) and 4-amidino-2,5-dimethyl-1-(5-isoquinolinesulfonyl)piperazine,i.e., Compound (49) as set forth in Table 22.

The equation is as follows; ##STR53##

                                      TABLE 21                                    __________________________________________________________________________     No.Run                                                                                      ##STR54##       (°C.)TemperatureReaction                                                      (hour)TimeReaction                      __________________________________________________________________________    1  4.55       2    H     4.77 0˜5                                                                            1                                                           H                                                                             H                                                          2  1.82       1    CH.sub.3                                                                            2.30 0˜5                                                                            1                                                           H                                                                             H                                                          3  1.82       1    H     2.46 0˜5                                                                            1                                                           CH.sub.3                                                                      CH.sub.3                                                   __________________________________________________________________________

                                      TABLE 22                                    __________________________________________________________________________              ##STR55##                                                                       R.sub.5      Mass IR Absorption                                   Run                                                                              Compound R.sub.6                                                                           Yield    Spectrum                                                                           Spectrum                                                                              NMR Spectrum                            No.                                                                              No.   n  R.sub.7                                                                           [g   (%)]                                                                              (m/e)                                                                              (ν.sub.max, cm.sup.-1)                                                             (D.sub.2 O, DCl, δ)               __________________________________________________________________________    1  45    2  H   4.80 (72)                                                                              333, 316                                                                           3320, 1680                                                                            1.5˜1.9 (2H), 2.6˜3.7                   H            292, 221                                                                           1590, 1160                                                                            (8H), 7.5˜8.3 (1H),                           H                         8.4˜8.9 (4H), 9.8 (1H)            2  47    1  CH.sub.3                                                                          3.51 (85)                                                                              333, 316                                                                           3330, 1680                                                                            1.3 (3H), 2.4˜3.6 (7H)                        H            292, 221                                                                           1590, 1160                                                                            7.8˜8.2 (1H), 8.3˜8.9                   H                         (4H), 9.8 (1H)                          3  49    1  H   2.19 (79)                                                                              347, 330                                                                           3340, 1680                                                                            0.8˜1.4 (6H), 2.5˜4.2                   CH.sub.3     306, 221                                                                           1590, 1160                                                                            (6H), 7.8˜8.3 (1H),                           CH.sub.3                  8.4˜8.9 (4H), 9.8                 __________________________________________________________________________                                          (1H)                                

EXAMPLE 10

In 10 ml of water were dissolved 1.00 g ofN-(2-aminoethyl)-5-isoquinolinesulfonamide and 2.91 g of2-methylthio-2-imidazoline hydrobromide, and to the mixture solution wasadded 0.83 g of potassium carbonate. After the solution was heated atreflux for three hours, the reaction mixture solution was cooled to 25°C., and the crystals precipitated were separated by filtration. Thecrystalline residue thus obtained was recrystallized from methanol togive 0.95 g of 2-[2-(5-isoquinolinesulfonamide)ethylamino]-2-imidazolinein a yield of 75%.

Mass spectrum (m/e): 319, 235, 207, 192 and 128.

NMR spectrum (DCl,D₂ O,δ): 3.0˜3.5 (4H), 3.9 (4H), 8.0˜8.3 (1H), 8.7˜9.1(4H) and 9.9, (1H)

IR absorption spectrum (.sup.ν max, cm⁻¹): 3500, 3300, 1700, 1630, 1340,1170 and 1140.

The same procedures as described above were repeated using the compoundsof Formula (III) as set forth in Table 23 under the reaction conditionsas set forth in Table 23, and there were obtained2-[2-(5-isoquinolinesulfonamido)ethylamino]-1,4,5,6-tetrahydropyrimidine,i.e., Compound (51),N-[2-2,3-dimethylguanidio)ethyl]-5-isoquinolinesulfonamide, i.e.,Compound (53),N-[2-(2,3-diethylguanidino)ethyl]-5-isoquinolinesulfonamide, i.e.,Compound (54), N-[2-(3-methylguanidino)ethyl]-5-isoquinolinesulfonamide,i.e., Compound (52) andN-[2-(3-ethylguanidino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound(55) as set forth in Table 24.

The equation is as follows; ##STR56##

                                      TABLE 23                                    __________________________________________________________________________     Run                                                                                           ##STR57##    K.sub.2 CO.sub.3                                                                  Reaction                                                                               Time Reaction                      No.                                                                              (g)          R.sub.3                                                                            R.sub.4                                                                            (g)                                                                              (g) Temperature                                                                           (hour)                               __________________________________________________________________________    1  1            CH.sub.2 CH.sub.2 CH.sub.2                                                              3.08                                                                             0.85                                                                              Reflux 3                                     2  1            CH.sub.3                                                                           CH.sub.3                                                                           2.94                                                                             0.85                                                                              Reflux 3                                     3  1            C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    3.27                                                                             0.85                                                                              Reflux 3                                     4  1            H    CH.sub.3                                                                           2.77                                                                             0.85                                                                              Reflux 3                                     5  1            H    C.sub.2 H.sub.5                                                                    2.94                                                                             0.85                                                                              Reflux 3                                     __________________________________________________________________________

                                      TABLE 24                                    __________________________________________________________________________                ##STR58##                                                         Compound             Yield   Mass Spectrum                                                                         IR Absorption Spectrum                                                                    NMR Spectrum                 Run No.                                                                            No.   R.sub.3                                                                            R.sub.4                                                                            [g  (%)]                                                                              (m/e)   (ν.sub.max, cm.sup.-1)                                                                 (D.sub.2 O, DCl,             __________________________________________________________________________                                                     δ)                     1    51    CH.sub.2 CH.sub.2 CH.sub.2                                                              1.02                                                                              (77)                                                                              334, 235                                                                              1700, 1620  1.5˜1.7 (2H),                                                           3.0˜3.3                                             207, 192                                                                              1340, 1170  (8H), 8.7˜9.1                                                           (4H), 9.9                                                 128     1140        (1H), 8.0˜8.3                                                           (1H)                         2    53    CH.sub.3                                                                           CH.sub.3                                                                           1.09                                                                              (85)                                                                              322, 235                                                                              1700, 1630  3.0˜3.3 (10H),                                                          8.7˜9.1                                             207, 192                                                                              1340, 1160  (4H), 9.9 (1H),                                                               8.0˜8.3                                             128     1130        (1H)                         3    54    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    1.25                                                                              (90)                                                                              350, 235                                                                              1690, 1630  1.4 (6H), 3.0˜3.3                                                       (8H),                                                     207, 192                                                                              1350, 1150  8.0˜8.3 (1H),                                                           8.7˜9.1                                             128     1120        (4H), 9.9 (1H)               4    52    H    CH.sub.3                                                                           0.966                                                                             (79)                                                                              308, 235                                                                              1680, 1640  3.0˜3.3 (7H),                                                           8.0˜8.3                                             207, 192                                                                              1350, 1150  (1H), 8.7˜9.1                                                           (4H),                                                     128     1120        9.9 (1H)                     5    55    H    C.sub.2 H.sub.5                                                                    1.09                                                                              (85)                                                                              322, 235                                                                              1680, 1630  1.4 (3H), 3.0˜3.3                                                       (6H),                                                     207, 192                                                                              1350, 1160  8.0˜8.3 (1H),                                                           8.7˜9.1                                             128     1140        (4H), 9.9                    __________________________________________________________________________                                                     (1H)                     

EXAMPLE 11

In 20 ml of methanol was suspended 1.0 g ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide, i.e., Compound (2), thecrystalline residue was dissolved with 7.5 ml of 1N aqueoushydrochloride solution. The reaction mixture solution was condensed todryness under reduced pressure, the crystalline residue thus obtainedwas recrystallized from methanol to give 1.12 g ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide dihydrochloride in ayield of 90%.

Elemental Analysis Value: Calcd. (%): C 39.35; H 4.68; N 19.12; S 8.75;Cl 19.36, Found (%): C 39.4; H 4.8; N 19.0; S 8.7; Cl 19.4.

The same procedures as described above were repeated using the compoundsof Formula (I) as set forth in Table 25 under the reaction conditions asset forth in Table 25, and there were obtained dihydrochloric acid saltsof the compounds of Formula (I) as set forth in Table 25.

The equation is as follows; ##STR59##

                                      TABLE 25                                    __________________________________________________________________________         Compound of                                                                           Compound                                                                            p                                                          Run No.                                                                            Formula (I) (g)                                                                       No.   q    R    [g   (%)] Calcd. (%)   Found                     __________________________________________________________________________                                                        (%)                       1    1       3     0    H    1.11 (90) C41.06; H 5.04; N                                                                          C41.2; H 5.1; N 18.3                         2                   Cl 18.65; S8.43                                                                            Cl 18.5; S8.4             2    "       4     0    "    1.09 (89) C42.65; H 5.37; N                                                                          C42.5; H 5.4; N 17.7                         3                   Cl 17.98; S8.13                                                                            Cl 17.8 S8.0              3    "       5     0    "    1.11 (91) C44.12; H 5.68, N                                                                          C44.0; H 5.7; N 17.2                         4                   Cl 17.36; S7.85                                                                            Cl 17.3; S --             4    "       6     0    "    1.03 (85) C45.50; H 5.97; N                                                                          C--; H--; N --                               5                   Cl 16.79; S7.59                                                                            Cl--; S --                5    "       7     0    "    1.06 (89) C48.00; H 6.49, N                                                                          C47.9; H 6.5; N 15.4                         7                   Cl 15.74; S7.12                                                                            Cl 15.8; S --             6    "       8     0    "    1.03 (87) C50.42; H 6.56; N                                                                          C50.6; H 6.6; N 14.7                         9                   Cl 14.88; S6.73                                                                            Cl 14.9; S6.7             7    1       9     0    CH.sub.3                                                                           1.13 (91) C41.06; H 5.04; N                                                                          C41.1; H 5.1; N 18.5                         1                   Cl 18.65; S8.43                                                                            Cl 18.8; S --             8    "       10    0    C.sub.2 H.sub.5                                                                    1.10 (90) C42.65; H 5.37; N                                                                          C42.7; H 5.5; N 17.8                         1                   Cl 17.98; S8.13                                                                            Cl 18.0; S --             9    "       13    0    n-C.sub.4 H.sub.9                                                                  1.06 (88) C45.50; H 5.97; N                                                                          C45.6; H 5.9; N 16.5                         1                   Cl 16.79; S7.59                                                                            Cl 16.8; S --             10   "       16    1    CH.sub.3                                                                           1.11 (90) C41.06; H 5.09; N                                                                          C41.0; H 5.1; N 18.4                         0                   Cl 18.65 S8.43                                                                             Cl 18.7; S8.5             11   "       17    1    C.sub.2 H.sub.5                                                                    1.12 (91) C42.65; H 5.37; N                                                                          C--; H --; N --                              0                   Cl 17.98; S8.13                                                                            Cl--; S --                12   "       19    1    i-C.sub.3 H.sub.7                                                                  1.05 (86) C44.12; H 5.68; N                                                                          C44.0; H 5.7; N 17.1                         0                   Cl 17.36; S7.85                                                                            Cl 17.3; S --             13   1       23    0    Ph   1.05 (88) C48.87; H 4.79; N                                                                          C48.8; H 4.7; N 15.8                         1                   Cl 16.03; D 7.25                                                                           Cl 15.9; S --             14   "       24    0    PhCH.sub.2                                                                         1.04 (87) C50.00; H 5.08; N                                                                          C50.0; H 5.2; N 15.4                         1                   Cl 15.54; S7.02                                                                            Cl 15.5; S --             15   "       25    1    Ph   1.09 (91) C48.87; H 4.79; N                                                                          C48.9; H 4.7; N 15.7                         0                   Cl 16.03; S7.25                                                                            Cl 16.0; S --             16   "       35    2    PhCH.sub.2                                                                         1.01 (85) C50.00; H 5.08; N                                                                          C49.9; H 5.1; N 15.3                         0                   Cl 15.54; S7.02                                                                            Cl 15.4; S --             17   "       28    1    CH.sub.3                                                                           1.09 (89) C42.65; H 5.37; N                                                                          C42.8; H 5.4; N 17.8                         1                   Cl 17.98; S8.13                                                                            Cl 18.0; S --             18   "       31    1    Ph   1.01 (85) C50.00; H 5.08; N                                                                          C49.9; H 5.0; N 15.5                         1                   Cl 15.54; S7.02                                                                            Cl 15.6; S --             19   1       34    1    PhCH.sub.2                                                                         1.03 (87) C51.07; H 5.36; N                                                                          C51.1; H 5.4; N 14.8                         1                   Cl 15.07; S6.82                                                                            Cl 15.1; S --             20   "       36    2    CH.sub.3                                                                           1.07 (88) C44.12; H 5.68; N                                                                          C44.0; H 5.6; N 17.1                         1                   Cl 17.36; S7.85                                                                            Cl 17.4; S --             21   "       37    2    Ph   1.07 (90) C51.07; H 5.36; N                                                                          C51.0; H 5.4; 14.9                           1                   Cl 15.07; S6.82                                                                            Cl 15.0; S --             22   "       38    3    PhCH.sub.2                                                                         1.07 (91) C53.01; H 5.86; N                                                                          C53.3; H 5.9; N 14.0                         1                   Cl 14.22; S6.43                                                                            Cl 14.1; S --             23   "       39    1    PhCH.sub.2                                                                         1.07 (91) C53.01; H 5.86; N                                                                          C53.1; H 5.9; N 14.1                         3                   Cl 14.22; S6.43                                                                            Cl 14.2; S                __________________________________________________________________________                                                        --                    

EXAMPLE 12

50 ml of methanol was suspended 20.5 g ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide, and the mixture solutionwas dissolved completely with 30 ml of methanol solution containing13.32 g of p-toluenesulfonic acid hydrate. The methanol was distilledtherefrom under reduced pressure, the crystalline residue wasrecrystallized from water to give 24.8 g ofN-(2-guanidinoethyl)-5-isoquinoline-sulfonamide-p-toluenesulfonate in ayield of 76.1%. The melting point of the compound was the range from148° C. to 149° C.

EXAMPLE 13

In 55 ml of water was suspended 20.5 g ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide, the crystalline residuewas dissolved by slowly adding of 8.2 ml of an aqueous concentratedhydrochloric acid solution. The pH of the aqueous layer was adjusted to6.8 with 3.2 ml of a 10N aqueous sodium hydroxide solution by dropwiseaddition at a temperature of 30° C. to 40° C., and the mixed solutionwas stirred for a night. The crystalline residue thus obtained wasseparated by filtration, and the residue was recrystallized from 50 mlof water to give 18.9 g ofN-(2-guanidinoethyl)-5-isoquinolinesulfonamide monohydrochloride in ayield of 82%. The melting point of the compound was 236° C.

Elemental Analysis Value: Calcd. (%): C 43.70; H 4.89; N 21.23; Cl10.75. Found (%): C 44.01; H 5.00; N 20.95; Cl 10.92.

Relaxation of Mesenteric Artery

After a home bred rabbit of a Japanese species weighing about 3 Kg wassubjected to bloodletting, resulting in death and then to abdominalincision, the mesenteric artery was taken out, cut into helicoids of 2mm×25 mm and suspended in a 20 ml organ bath filled with aKrebs-Henseleit solution into which a mixed gas of 95% by volume of O₂and 5% by volume of CO₂ was introduced and one end of the artery wasconnected with an isometric transducer. When a load of 1.5 g was appliedto the artery, the contraction and the relaxation of the artery wererecorded as a weight on the transducer (a product of Nippon Koden K.K.,Japan, "FD Pickup TB-912T"). The relaxation of the mesenteric artery wasobserved by adding the isoquinolinesulfonamide derivatives and theirpharmaceutically acceptable acid addition salts of this invention to themesenteric artery at the condition of about one half of the maximumcontraction with KCl concentration of 15-20 mM. When the completerelaxation of the mesenteric artery was designated 100%, theconcentration of the isoquinolinesulfonamide derivatives and theirpharmaceutically acceptable acid addition salts which brought about arelaxation of 50% is shown in Table 26.

                  TABLE 26                                                        ______________________________________                                                Relaxation              Relaxation                                            of Mesenteric           of Mesenteric                                 Compound                                                                              Artery ED.sub.50                                                                            Compound  Artery ED.sub.50                              Nos.    (μM)       Nos.      (μM)                                       ______________________________________                                         2      1              6        4                                              3      2              7        10                                             4      2              8        15                                             5      3              9        3                                             10      5             39        13                                            13      13            50        20                                            16      3             51        25                                            17      10            52        7                                             19      15            53        10                                            23      8             54        12                                            24      10            55        5                                             25      10            41        8                                             28      3             43        5                                             31      2             44        0.6                                           34      2             45        2                                             35      5             49        1                                             36      5                                                                     37      10                                                                    38      11                                                                    ______________________________________                                    

Effect on Blood Flow Volume of Femoral and Vertebral Arteries of Dogs,and an hypotensive action

The effect on the vasodilatation of the femoral and vertebral arterieswas measured by anesthetizing a dog of mixed breed weighing 8 to 15 Kgby an intravenous administration of 35 mg/Kg of pentbarbital, providingan acute type probe (a product of Nippon Koden K.K., Japan) with thefemoral and vertebral arteries, administering to the femoral veinthrough a polyethylene tube inserted into the femoral vein side chain,measuring the blood flow volume with an electromagnetic blood flowmeter(a product of Nippon Koden K.K., Japan, "MFV-1200") and measuring thechange of blood pressure. The results are shown in Table 27.

                                      TABLE 27                                    __________________________________________________________________________          Amount of                                                                             Increased Blood                                                                        Increased Blood                                              Intravenous                                                                           Flow Volume in                                                                         Flow Volume in                                                                         Average Decreased                                                                       Duration                            Compound                                                                            Administration                                                                        Femoral Artery                                                                         Vertebral Artery                                                                       Blood Pressure                                                                          Time                                Nos.  (mm/Kg) (%)      (%)      (mmHg)    (Min.)                              __________________________________________________________________________    2     1       37       95       32        >30                                 31    1       30       75       15        28                                  43    1       32       68       15        25                                  44    0.5     29       60       50        >30                                 50    1       19       65       10        21                                  __________________________________________________________________________

Acute Toxicity

The acute toxicity of the N-(2-guanidinoethyl)-5-isoquinolinesulfonamidedihydrochloride was measured by giving male ddY-strain mouse and rat anintravenous administration and an oral administration. The results areshown in Table 28.

                  TABLE 28                                                        ______________________________________                                        LD.sub.50 (mg/Kg)                                                             Intravenous            Oral                                                   administration         administration                                         ♂ mouse                                                                            ♂ rat   ♂ mouse                                                                            ♂ rat                                   ______________________________________                                        59        64           1480      1156                                         ______________________________________                                    

The acute toxicity of the hydrochloric acid salt of other compounds wasmeasured by giving male ddY-strain mice an intravenous administration.The results are shown in Table 29.

                  TABLE 29                                                        ______________________________________                                        Compound                                                                      Nos.          LD.sub.50 (mg/Kg)                                               ______________________________________                                        31            80                                                              43            66                                                              44            12                                                              ______________________________________                                    

What is claimed is:
 1. A compound of Formula (I): ##STR60## wherein A isa single bond; a C₁ -C₁₀ alkylene group; or a C₁ -C₁₀ alkylene grouphaving a C₁₋₁₀ alkyl, phenyl or phenylalkyl group having a C₁₋₂ alkylportion substituent;R₁ and R₂ are linked directly to form an ethylenegroup unsubstituted or substituted with a C₁₋₄ alkyl substituent; R₃ andR₄ are each a hydrogen atom, or a C₁₋₆ alkyl group and pharmaceuticallyacceptable acid addition salts thereof.
 2. The compound of claim 1,wherein A is an unsubstituted C₂ -C₃ alkylene group, a C₂ -C₃ alkylenegroup having a C₁₋₁₀ alkyl phenyl or phenylalkyl group having a C₁₋₂alkyl portion substituent; and R₃ and R₄ each is a hydrogen atom.
 3. Thecompound of claim 2 wherein A is an unsubstituted C₂₋₃ alkylene group;and R₁ and R₂ are linked directly, to form an unsubstituted ethylenegroup.
 4. The compound of claim 2 wherein A is a C₂₋₃ alkylene grouphaving one C₁₋₁₀ alkyl substituent, and R₁ and R₂ are linked directly toform an unsubstituted ethylene group.
 5. The compound of claim 4 whereinA is a C₂₋₃ alkylene group having one C₁₋₄ alkyl substituent.
 6. Thecompound of claim 2 wherein A is a C₂₋₃ alkylene group having one C₁-C₁₀ alkyl substituent; and R₁ and R₂ are linked directly to form anethylene group substituted with a C₁₋₄ alkyl substituent.
 7. Thecompound of claim 6 wherein A is a C₂₋₃ alkylene group having one methylgroup; and R₁ and R₂ are linked directly to form an ethylene groupsubstituted with a methyl group.
 8. The compound of claim 1 wherein A isC₂₋₃ alkylene group or a C₂₋₃ alkylene group having a C₁₋₄ alkylsubstituent; and R₃ and R₄ are each a hydrogen atom.